Kaempferol induces hepatocellular carcinoma cell death via endoplasmic reticulum stress-CHOP-autophagy signaling pathway Kaempferol induces hepatocellular carcinoma cell death via endoplasmic reticulum stress-CHOP-autophagy signaling pathway

Background and Aim. Dysbiosis of gut microbiota is important in the development of hepatocellular carcinoma (HCC). However, little is known about whether and how dysbiosis impacts HCC progression. This cross-sectional study is aimed at evaluating microbiome dysbiosis, gut damage, and microbial translocation in different stages of HCC. Method. This study included 74 Chinese male patients with HCC. They were divided into early ( ), intermediate ( ), and terminal ( ) groups, referred to as Barcelona Clinic Liver Cancer stage 0+A, B, and C+D, respectively. Paired fecal and plasma samples were collected. Microbial composition and profiles were analyzed by 16S rRNA gene sequencing. The levels of gut damage marker (regenerating islet-derived protein 3α (REG3α)) and microbial translocation markers (soluble CD14 (sCD14), lipopolysaccharide-binding protein (LBP), peptidoglycan recognition proteins (PGRPs)) were determined in plasma samples of patients by ELISA. Twenty plasma cytokine and chemokines were determined by Luminex. Results. In early, intermediate, and terminal groups, the abundance of the Bifidobacteriaceae family decreased significantly (3.52%, 1.55%, and 0.56%, respectively, ), while the abundance of the Enterococcaceae family increased significantly (1.6%, 2.9%, and 13.4%, respectively, ). Levels of REG3α and sCD14 were markedly elevated only in the terminal group compared with the early ( and ) and intermediate groups ( and ). The level of LBP significantly increased in the intermediate ( ) and terminal ( ) groups compared with the early group. The PGRP levels were elevated only in the terminal group compared with the early group ( ). The ratio of Enterococcaceae to Bifidobacteriaceae was significantly associated with the levels of REG3α, LBP, sCD14, and PGRPs. With HCC progression, increased levels of inflammatory cytokines accompanied by a T cell-immunosuppressive response and microbial translocation were observed. Conclusion. Gut microbiota compositional and functional shift, together with elevated gut damage and microbial translocation, may promote HCC development by stimulating inflammatory response and suppressing T cell response.

Background: Recent studies indicated that the neutrophil percentage-to-albumin ratio (NPAR) was a predictor of mortality in several diseases. There has been no evidence to prove the predictive function of NPAR in patients with liver cirrhosis. Therefore, this study aimed to investigate the association between NPAR and clinical outcomes in cirrhotic patients. Methods: We retrospectively recruited hospitalized decompensated cirrhotic patients from the tertiary grade-A hospital. Patients with malignancy or severe cardiac, respiratory and kidney diseases were excluded. Demographical data, liver functions, complications and outcomes of cirrhosis were recorded. NPAR was calculated through the ratio of neutrophil percentage (%)/serum albumin concentration (g/dL) at admission to the hospital. Cox proportional hazards models were performed to evaluate the prognostic values of NPAR, and subgroup analyses were utilized to ensure stable results. Results: A total of 376 patients with decompensated liver cirrhosis at baseline were enrolled. The liver dysfunction, cirrhosis-related complications and mortality rate increased along with the tertiles of NPAR. In multivariate analysis, higher NPARs were independently associated with increased risk of mortality in patients with liver cirrhosis after adjustments for confounding factors (tertile 3 versus tertile 1: adjusted HR = 1.92; 95% CI, 1.04–3.56; P trend = 0.008) and each unit increase of NPAR implicated a 4% increase risk of mortality. Subgroup analysis demonstrated no significant interactions in most subgroups. Conclusion: Increased NPAR was independently correlated with a higher risk of mortality in patients with liver cirrhosis.

Patatin-like phospholipase domain-containing 3 (PNPLA3) rs738409 polymorphism (I148M) is strongly associated with non-alcoholic steatohepatitis and advanced fibrosis; however, the underlying mechanisms remain largely unknown. In this study, we investigated the effect of PNPLA3-I148M on the activation of hepatic stellate cell line LX-2 and the progression of liver fibrosis. Immunofluorescence staining and enzyme-linked immunosorbent assay were used to detect lipid accumulation. The expression levels of fibrosis, cholesterol metabolism, and mitochondria-related markers were measured via real-time PCR or western blotting. Electron microscopy was applied to analyze the ultrastructure of the mitochondria. Mitochondrial respiration was measured by a Seahorse XFe96 analyzer. PNPLA3-I148M significantly promoted intracellular free cholesterol aggregation in LX-2 cells by decreasing cholesterol efflux protein (ABCG1) expression; it subsequently induced mitochondrial dysfunction characterized by attenuated ATP production and mitochondrial membrane potential, elevated ROS levels, caused mitochondrial structural damage, altered the oxygen consumption rate, and decreased the expression of mitochondrial-function-related proteins. Our results demonstrated for the first time that PNPLA3-I148M causes mitochondrial dysfunction of LX-2 cells through the accumulation of free cholesterol, thereby promoting the activation of LX-2 cells and the development of liver fibrosis.

To evaluate variations in coagulation, fibrinolysis and endothelial marker expression in cirrhotic patients and to explore their clinical value and predictive performance in cirrhotic patients with or without portal vein thrombosis (PVT), we performed a case-control study with 175 cirrhotic patients and 50 healthy individuals. 99 patients had PVT and another 76 patients did not. All participants were evaluated for plasma levels of conventional hemostatic markers. Thrombin-antithrombin complex (TAT), plasmin-α2-plasmin inhibitor complex (PIC), thrombomodulin (TM), tissue plasminogen activator inhibitor complex (t-PAIC), von Willebrand factor antigen (vWF: Ag) and coagulation factor Ⅷ (FⅧ: c) were also assessed and the ratio of TAT/t-PAIC was calculated. We analyzed differences in these biomarkers among the three groups and constructed receiver operating characteristic (ROC) curves. Patients with PVT exhibited significantly higher TAT and TAT/t-PAIC than cirrhotic patients without PVT (both P < 0.001). Areas under the curve (AUC) of ROC analyses for TAT and TAT/t-PAIC were 0.68 and 0.66, the cut-off levels were 1.55 ng/ml and 0.46, with sensitivities and specificities of 78.79% and 51.32% regarding TAT, 39.8% and 90.79% regarding TAT/t-PAIC. Levels of FⅧ: c and vWF: Ag in patients with PVT were significantly lower than those without PVT (p = 0.026 and p = 0.027, respectively). The AUC^ROC, cut-off level, sensitivity and specificity of FⅧ: c were 0.64, 111.1%, 66.67% and 60%, respectively. For vWF: Ag they were 0.61, 429%, 89.66% and 38.71%, respectively. Cirrhotic patients have disorders of coagulation, fibrinolysis and the endothelial system. TAT, TAT/t-PAIC, FⅧ: c and vWF: Ag can be used as potential biomarkers for predicting PVT in cirrhotic patients.

Purpose of review: Cirrhotic cardiomyopathy (CCM) is a well-recognized entity. When patients with CCM encounter challenges such as liver transplantation, overt cardiac dysfunction manifests, leading to morbidity and mortality. Although revised diagnostic criteria for CCM have recently been proposed, these still need to be validated. Recent findings: Previous reviews have summarized the mechanisms of CCM, such as abnormalities of the β-adrenergic pathway, cardiac plasma membrane biophysical and biochemical properties, and electrophysiological changes. Cardiomyocyte apoptosis, inflammation, and oxidative stress also play important roles. The present review details further mechanisms of CCM, which include myosin heavy chain isoform shifts and abnormalities in cellular calcium transients. Additionally, we review recent studies on therapeutic strategies. Recent work underscores the importance of CCM in the natural history of the immediate and medium-term postoperative period after liver transplantation. Appropriate management strategies for CCM remain the area of greatest unmet need, requiring much further research. Summary: CCM is a clinically relevant syndrome affecting patients with cirrhosis, leading to increased morbidity and mortality. New diagnostic criteria have been recently proposed by an expert working group. The pathogenic mechanisms remain incompletely clarified and optimal management strategies need much further study.